Back to Search
Start Over
Development of 3,5-Dinitrophenyl-Containing 1,2,4-Triazoles and Their Trifluoromethyl Analogues as Highly Efficient Antitubercular Agents Inhibiting Decaprenylphosphoryl-β-d-ribofuranose 2'-Oxidase
- Source :
- Journal of medicinal chemistry. 62(17)
- Publication Year :
- 2019
-
Abstract
- We report herein the discovery of 3,5-dinitrophenyl 1,2,4-triazoles with excellent and selective antimycobacterial activities against Mycobacterium tuberculosis strains, including clinically isolated multidrug-resistant strains. Thorough structure-activity relationship studies of 3,5-dinitrophenyl-containing 1,2,4-triazoles and their trifluoromethyl analogues revealed the key role of the position of the 3,5-dinitrophenyl fragment in the antitubercular efficiency. Among the prepared compounds, the highest in vitro antimycobacterial activities against M. tuberculosis H37Rv and against seven clinically isolated multidrug-resistant strains of M. tuberculosis were found with S-substituted 4-alkyl-5-(3,5-dinitrophenyl)-4H-1,2,4-triazole-3-thiols and their 3-nitro-5-(trifluoromethyl)phenyl analogues. The minimum inhibitory concentrations of these compounds reached 0.03 μM, which is superior to all the current first-line anti-tuberculosis drugs. Furthermore, almost all compounds with excellent antimycobacterial activities exhibited very low in vitro cytotoxicities against two proliferating mammalian cell lines. The docking study indicated that these compounds acted as the inhibitors of decaprenylphosphoryl-β-d-ribofuranose 2'-oxidase enzyme, which was experimentally confirmed by two independent radiolabeling experiments.
- Subjects :
- Models, Molecular
Hydrocarbons, Fluorinated
Stereochemistry
medicine.drug_class
Antitubercular Agents
Antimycobacterial
01 natural sciences
Mycobacterium tuberculosis
03 medical and health sciences
chemistry.chemical_compound
Structure-Activity Relationship
Bacterial Proteins
Drug Development
Drug Discovery
medicine
Structure–activity relationship
030304 developmental biology
chemistry.chemical_classification
0303 health sciences
Oxidase test
Trifluoromethyl
biology
Dose-Response Relationship, Drug
Molecular Structure
Chemistry
Triazoles
biology.organism_classification
0104 chemical sciences
010404 medicinal & biomolecular chemistry
Alcohol Oxidoreductases
Dinitrobenzenes
Enzyme
Docking (molecular)
Molecular Medicine
Dinitrophenyl
Subjects
Details
- ISSN :
- 15204804
- Volume :
- 62
- Issue :
- 17
- Database :
- OpenAIRE
- Journal :
- Journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....6248d5a3ac3569c19e89b00aa09d5b33